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Synthetic Explorations in the Pursuit of a Rapid, Photoactivatable, Nitroxyl

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Synthetic Explorations in the Pursuit of a Rapid, Photoactivatable, Nitroxyl SYNTHETIC EXPLORATIONS IN THE PURSUIT OF A RAPID, PHOTOACTIVATABLE NITROXYL DONOR A thesis submitted to the Kent State University Honors College in partial fulfillment of the requirements for Departmental Honors by Mark Wesley Campbell April, 2017 Thesis written by Mark Wesley Campbell Approved by ________________________________________________________________, Advisor ________________________________________________________________, Advisor ________________________________________________________________, Chair, Department of Chemistry & Biochemistry Accepted by _____________________________________________________, Dean, Honors College ii TABLE OF CONTENTS LIST OF FIGURES……………………………………………………...….……………vi LIST OF TABLES………………………………………………………………………..ix ACKNOWLEDGMENTS………………………………………………….......................x CHAPTER 1. INTRODUCTION..............................................................................................1 1.1 Chemical Properties of Nitroxyl ......................................................2 1.1.1 Acid/Base Chemistry of Nitroxyl ....................................................2 1.1.2 HNO Dimerization ...........................................................................3 1.1.3 HNO Thiophilicity ...........................................................................3 1.1.4 Nitroxyl Coordination Chemistry. ...................................................4 1.1.5 Nitroxyl’s Reactions with Biomolecules .........................................5 1.2 Biological Properties and Therapeutic Uses of HNO ......................6 1.2.1 Nitroxyl as a Vasorelaxant ...............................................................6 1.2.2 Nitroxyl as a Positive Inotrope ........................................................8 1.2.3 Pharmacology of HNO ....................................................................8 1.2.4 Endogenous Production of HNO .....................................................9 1.3 Detection of HNO ..........................................................................12 1.3.1 Copper-based HNO Probes ............................................................12 1.3.2 TEMPO HNO Probes ....................................................................12 iii 1.3.3 Phosphine-based HNO Probes .......................................................13 1.3.4 Electrochemical HNO Detection ...................................................13 1.4 HNO Donors ..................................................................................14 1.4.1 Angeli’s Salt...................................................................................14 1.4.2 Diazeniumdiolates..........................................................................15 1.4.3 Acyloxy and Acyl Nitroso Compounds .........................................16 1.4.4 Protected Hydroxylamines .............................................................17 1.5 HNO Donors Developed by the Sampson/Seed/Brasch Group .....19 1.5.1 Design of Photoactivatable HNO Donors ......................................19 1.5.2 First Generation 3,2-HNM HNO Donors ......................................21 1.5.3 Strategies for the Improvement of First-Generation Donor 24a ....25 1.6 Thesis Project Goals ......................................................................28 2. RESULTS AND EXPERIMENTAL DISCUSSION ......................................29 2.1 Primary Objectives.........................................................................29 2.2 Synthesis of Secondary Alcohol Intermediate 32 ..........................29 2.3 Exploration of the Mitsunobu Reaction .........................................30 2.3.1 Initial Optimization of the Mitsunobu Reaction of Alcohol 32 .....30 2.3.2 Mitsunobu Reaction with a 2,6-disubstituted Analog of 32 ..........33 2.3.3 Alternative Methods: Oxaziridine Amination ...............................34 2.3.4 Literature Regarding Mitsunobu Reaction of Sterically Hindered Alcohols .........................................................................................37 iv 2.3.5 Detailed Exploration of the Mitsunobu Reaction ..........................45 2.3.6 Synthesis of New NHPs .................................................................51 2.6 Synthesis and Analysis of Donor 36 ..............................................56 2.6.1 Completion of the Synthesis of Donor 36......................................56 2.6.2 Photochemical Analysis of Potential HNO Donor 36 ...................59 2.7 Future Goals ...................................................................................62 3. EXPERIMENTAL DETAILS .........................................................................64 3.1 General procedures ........................................................................64 3.2 Experimental details.......................................................................66 REFERENCES ........................................................................................115 NMR Spectra ...........................................................................................122 v LIST OF FIGURES Figure 1.1: Lewis structure of nitroxyl ................................................................................1 Figure 1.2: The dimerization/degradation of HNO..............................................................3 Figure 1.3: The reactions of HNO with thiols .....................................................................3 Figure 1.4: The reactions of HNO with metals ....................................................................5 Figure 1.5: HNO production from cyanamide in a biological system .................................9 Figure 1.6: Biosynthesis of HNO from the NOS intermediate: N-hydroxy-L-arginine ....10 Figure 1.7: Reaction of NO with thiols with possible HNO intermediacy ........................10 Figure 1.8: Production of HNO from NOS and CBS products with subsequent TRPA1 activation ............................................................................................................................11 Figure 1.9: Mechanism of electrochemical HNO detection via cobalt porphyrin .............14 Figure 1.10: The aqueous degradation of Angeli’s salt .....................................................14 Figure 1.11: Structures of various diazeniumdiolates ........................................................15 Figure 1.12: Hydroylsis of acyloxy nitroso compounds to release HNO ..........................16 Figure 1.13: Mechanism of HNO release from donors developed by King’s group .........17 Figure 1.14: Mechanism of HNO release from PA ...........................................................18 Figure 1.15: Acidity constants and HNO release rates for various PA analogs ................18 Figure 1.16: HNO donors developed by the Toscano group .............................................19 Figure 1.17: HNO donor using a photolabile (3-hydroxy-2-napthyl)methyl (3,2-HNM) protecting group .................................................................................................................20 Figure 1.18: Mechanism of 3,2-HNM photocleavage .......................................................20 Figure 1.19: Synthetic scheme for the preparation of first-generation HNO donors .........21 vi Figure 1.20: 19F NMR spectra monitoring the progress of the photolysis of donor 24a ...22 Figure 1.21: Proposed mechanism for the generation of the two observed products from the photodecomposition of donor 24a ...............................................................................23 Figure 1.22: Base-mediated decomposition of 24d ...........................................................24 Figure 1.23: UV-Vis spectra showing the reaction of HNO with H2OCbl(III) .................25 Figure 1.24: Incorporation of a benzylic substituent as a potential strategy to improve selectivity for HNO generation ..........................................................................................26 Figure 1.25: Synthetic scheme for the preparation of donor 39 ........................................26 Figure 1.26: Products of the LiAlH4 reduction of ester 18 ................................................27 Figure 2.1 Preliminary steps in the synthesis of donor 36 .................................................30 Figure 2.2: Attempted acid-catalyzed substitution of 32 ...................................................33 Figure 2.3: Mitsunobu reaction of (-)-menthol with benzoic acid .....................................33 Figure 2.4: Synthetic preparation of 2,6-disubstituted analogs .........................................34 Figure 2.5: Proposed mechanism of alcohol amination via oxaziridine ............................35 Figure 2.6: Preparation and application of Ellman’s oxaziridine ......................................36 Figure 2.7: Mitsunobu esterification of sterically hindered alcohols with chloroacetic acid .....................................................................................................................................40 Figure 2.8: Mechanism of the Mitsunobu esterification ....................................................40 Figure 2.9: Brønsted plot of log k vs pKa illustrating the rates of alcohol activation and SN2 reaction with various carboxylic acids .......................................................................43 Figure 2.10: Side reaction that occurs when the alcohol is omitted from the Mitsunobu reaction ...............................................................................................................................44
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